The present invention relates to synthetic or recombinant fucosylated oligosaccharides for use in the treatment or prophylaxis of an infection with a Norwalk-like Virus or a Rotavirus of a mammal.
The Norwalk-like viruses (NLV), also called Noroviruses, are non-enveloped viruses belonging to the calicivirus family. They are the most common cause of viral acute gatroenteritis in humans, and affect people of all age. The viruses are transmitted by fecally-contaminated food or water, by person-to-person contact, and via aerosolization of the virus and subsequent contamination of surfaces. An infection with Noroviruses is characterized by nausea, forceful vomiting, watery diarrhea, and abdominal pain. In particular very young children, elderly persons, and persons with weakened immune system are often in danger of dying when heavily infected. Noroviruses are highly contagious, and already few virus particles can cause an infection, which explains the rapid and excessive spread of the virus and of infected people. Also, due to their high resistance towards cleaning agents, Norovirus-breakouts are regularly observed in schools, clinics, senior homes, children day care centers, etc.
Norovirus-infections and their symptoms represent one of the most common causes of death worldwide for children under the age of three. In Germany, more than 15.000 infections have been reported for infants (age 0 to 12 months) in the year 2011 alone; with about 20 millions infections worldwide, more than 200.000 cases of death of infants are estimated to be caused by a Norovirus-infections.
While Norovirus-studies remain difficult due to the fact that no animal models exist, there has recently been developed a cell culture model for assessing their pathogenicity. Also, using recombinant virus particles and testing volunteers, the histo-blood groups antigens (abbreviated with HBGA) serving as receptors for Noroviruses have been identified. HBGA are complex oligosaccharides which are expressed on the surface of red blood cells, the gastric mucosa, of the respiratory passages, urogenital system and of the intestinal tract. The HBG antigen H1, which is encoded via FUC2, an alpha-1,2-fucosyltransferase, has been identified as the most important genetic predisposition: individuals with homocygous zero-mutant alleles for FUC2 have been shown as being resistant towards gastrointestinal infections of the Norovirus.
Although other studies have shown that up to 90% of the adults tested so far do have antibodies against Noroviruses, it has also been found out that the immunity lasts only as short as about 6 months, and, thus does not provide protection even against a reinfection with the same infectious strain.
Up to today, there is neither a vaccine available nor a causal therapy or a causal cure for norovirus-gastroenteritis; as a consequence, treatment of Norovirus-gastroenteritis is restricted to a supportive oral and eventually parenteral rehydration with electrolytes.
Similarly, infections with Rotavirus are the most common cause of severe diarrhea among infants and young children. Rotavirus is a genus of double-stranded RNA virus belonging to the Reoviridae family. By the age of five, nearly every child in the world has been infected with rotavirus at least once. As the Norovirus, the Rotavirus is transmitted by the fecal-oral route.
Rotavirus is usually an easily managed disease of childhood, but worldwide more than 450,000 children under five years of age still die from rotavirus infection each year, most of whom live in developing countries, and almost two million more become severely ill. Although the incidence and severity of rotavirus infections has declined in countries that have added rotavirus vaccine to their routine childhood immunisation policies, a vaccine that prevents infection of both, Norovirus and Rotavirus, would be highly valuable.
Marionneau et al. (“Norwalk Virus Binds to Histo-Blood Group Antigens Present on Gastroduodenal Epithelial Cells of Secretor Individuals”, Gastroenterology (2002) 122:1967-1977), have shown that recombinant Norwalk-virus-like particles use carbohydrates present on human gastroduodenal epithelial cells as ligands.
Further, Morrow et al. (“Human Milk Oligosaccharides are associated with protection against Diarrhea in Breast-fed Infants”, J. Pediatr. (2004) 145:297-303) have observed that Campylobacter and Calicivirus caused diarrhea occurred less often in infants who have been fed with milk containing high levels of 2-linked fucosyloligosaccharide as a percent of milk oligosaccharide.
In this connection, WO 2005/055944 discloses the use of oligosaccharide compositions, in particular of glycoproteins where 2-fucosyllactose is linked to human serum albumin, in the treatment of infections.
Although, with the above background, there are currently different approaches to treat or prevent infections with Noroviruses, no actual vaccine or composition has been provided yet that would have proven effective in such treatment/prophylaxis.
Thus, there still is a need for novel substances and compositions by means of which a Norovirus-infection can efficiently be treated or prevented, and it is an object of the invention to provide such a substance or composition containing such substance.